User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 253)
Drupal\Core\Render\Renderer->doRenderRoot() (Line: 143)
Drupal\Core\Render\Renderer->{closure:Drupal\Core\Render\Renderer::renderInIsolation():142}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 142)
Drupal\Core\Render\Renderer->renderInIsolation() (Line: 169)
Drupal\Core\Render\Renderer->doRenderPlaceholder() (Line: 206)
Drupal\Core\Render\Renderer->renderPlaceholder() (Line: 797)
Drupal\Core\Render\Renderer->replacePlaceholders() (Line: 265)
Drupal\Core\Render\Renderer->doRenderRoot() (Line: 143)
Drupal\Core\Render\Renderer->{closure:Drupal\Core\Render\Renderer::renderInIsolation():142}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 142)
Drupal\Core\Render\Renderer->renderInIsolation() (Line: 113)
Drupal\Core\Render\Renderer->renderRoot() (Line: 253)
Drupal\Core\Render\HtmlResponseAttachmentsProcessor->renderPlaceholders() (Line: 74)
Drupal\big_pipe\Render\BigPipeResponseAttachmentsProcessor->processAttachments() (Line: 106)
Drupal\canvas\Render\ImportMapResponseAttachmentsProcessor->processAttachments() (Line: 45)
Drupal\Core\EventSubscriber\HtmlResponseSubscriber->onRespond() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 216)
Symfony\Component\HttpKernel\HttpKernel->filterResponse() (Line: 204)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 169)
Drupal\Core\EventSubscriber\DefaultExceptionHtmlSubscriber->makeSubrequest() (Line: 119)
Drupal\Core\EventSubscriber\CustomPageExceptionHtmlSubscriber->makeSubrequestToCustomPath() (Line: 71)
Drupal\Core\EventSubscriber\CustomPageExceptionHtmlSubscriber->on403() (Line: 109)
Drupal\Core\EventSubscriber\HttpExceptionSubscriberBase->onException() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 241)
Symfony\Component\HttpKernel\HttpKernel->handleThrowable() (Line: 91)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 556)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 501)
Drupal\Core\Template\TwigExtension->escapeFilter() (Line: 73)
__TwigTemplate_903f906915f560ffb5a631ed1395e98b->doDisplay() (Line: 402)
Twig\Template->yield() (Line: 386)
Twig\Template->render() (Line: 51)
Twig\TemplateWrapper->render() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 556)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 556)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 556)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 162)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::renderResponse():157}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 157)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
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Nursing Drug Reference & Checker

🔍

Drug Reference Lookup

FDA label · Alerts · Nursing considerations · Beers · NIOSH

Patient Age

Used for Beers Criteria (65+) across both panels.

Drug Name (Brand or Generic)

Type 2+ letters for RxNorm autocomplete suggestions.

💊 RITUXAN HYCELA

☠ BLACK BOX WARNING

Generic: RITUXIMAB AND HYALURONIDASE

SUBCUTANEOUS FDA Label

☠

FDA BLACK BOX WARNING

WARNING: SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY WARNING: SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY See full prescribing information for complete boxed warning. S…

Quick reference

RouteSUBCUTANEOUS

ManufacturerGenentech, Inc.

SourceFDA Label

✅ Indications & Usage ›

1 INDICATIONS AND USAGE RITUXAN HYCELA is a combination of rituximab, a CD20-directed cytolytic antibody, and hyaluronidase human, an endoglycosidase, indicated for the treatment of adult patients with: Follicular Lymphoma (FL) ( 1.1 ) Relapsed or refractory, follicular lymphoma as a single agent Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy Non-progressing (including stable disease), follicular lymphoma as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy Diffuse Large B-cell Lymphoma (DLBCL) ( 1.2 ) Previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens Chronic Lymphocytic Leukemia (CLL) ( 1.3 ) Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC) Limitations of Use: Initiate treatment with RITUXAN HYCELA only after patients have received at least one full dose of a rituximab product by intravenous infusion. ( 1.4 , 2.1 , 5.4 ). RITUXAN HYCELA is not indicated for the treatment of non-malignant conditions. ( 1.4 )

1.1 Follicular Lymphoma (FL) RITUXAN HYCELA is indicated for the treatment of adult patients with: Relapsed or refractory, follicular lymphoma as a single agent. Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), follicular lymphoma as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.

1.2 Diffuse Large B-Cell Lymphoma (DLBCL) RITUXAN HYCELA is indicated for the treatment of adult patients w... [See full FDA label]

💉 Dosage & Administration ›

2 DOSAGE AND ADMINISTRATION For subcutaneous use only ( 2.1 ) All patients must receive at least one full dose of a rituximab product by intravenous infusion before receiving RITUXAN HYCELA by subcutaneous injection ( 2.1 ).

FL/DLBCL

Administer 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously according to recommended schedule ( 2.2 , 2.3 ). CLL: Administer 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) subcutaneously according to recommended schedule ( 2.4 ). Premedicate with acetaminophen and antihistamine before each dose; in addition, consider premedication with glucocorticoids ( 2.5 , 5.4 ) Administer specified volume into subcutaneous tissue of abdomen: ( 2.6 ) 11.7 mL from 1,400 mg/23,400 Units vial over approximately 5 minutes. 13.4 mL from 1,600 mg/26,800 Units vial over approximately 7 minutes. Observe 15 minutes following administration

2.1 Important Dosing Information RITUXAN HYCELA is for subcutaneous use only. RITUXAN HYCELA should only be administered by a healthcare professional with appropriate medical support to manage severe reactions that can be fatal if they occur. All patients must first receive at least one full dose of a rituximab product by intravenous infusion without experiencing severe adverse reactions before starting treatment with RITUXAN HYCELA. If patients are not able to receive one full dose by intravenous infusion, they should continue subsequent cycles with a rituximab product by intravenous infusion and not switch to RITUXAN HYCELA until a full intravenous dose is successfully administered [see Warnings and Precautions (5.4) ]. Refer to the prescribing information for a rituximab product for intravenous infusion for additional information. Premedicate before each dose of RITUXAN HYCELA [see Dosage and Administration (2.5) ] . Dose reductions of RITUXAN HYCELA are not recommended. When RITUXAN HYCELA is given in combination with chemotherapy dose, redu... [See full FDA label]

🚫 Contraindications ›

4 CONTRAINDICATIONS None None.

⚠️ Warnings & Precautions ›

5 WARNINGS AND PRECAUTIONS Hypersensitivity and other administration reactions: Local cutaneous reactions may occur more than 24 hours after administration. Interrupt injection if severe reaction develops. Premedicate before injection. ( 5.4 ) Tumor lysis syndrome: Administer aggressive intravenous hydration, anti hyperuricemic agents, monitor renal function. ( 5.5 ) Infections: Withhold and institute appropriate anti-infective therapy. ( 5.6 ) Cardiac adverse reactions: Discontinue in case of serious or life-threatening events. ( 5.7 ) Renal toxicity: Discontinue in patients with rising serum creatinine or oliguria. ( 5.8 ) Bowel obstruction and perforation: Consider and evaluate for abdominal pain, vomiting, or related symptoms. ( 5.9 ) Immunizations: Live virus vaccinations prior to or during treatment not recommended. ( 5.10 ) Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.11 )

5.1 Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab-containing products, including RITUXAN HYCELA. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. Discontinue RITUXAN HYCELA in patients who experience a severe mucocutaneous reaction. The safety of re-administration of a rituximab-containing product, including RITUXAN HYCELA, to patients with severe mucocutaneous reactions has not been determined .

5.2 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab-containing products. HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels... [See full FDA label]

🔴 Adverse Reactions ›

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Mucocutaneous reactions [see Warnings and Precautions (5.1) ] Hepatitis B reactivation including fulminant hepatitis [see Warnings and Precautions (5.2) ] Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3) ] Hypersensitivity and other administration reactions [see Warnings and Precautions (5.4) ] Tumor lysis syndrome [see Warnings and Precautions (5.5) ] Infections [see Warnings and Precautions (5.6) ] Cardiac arrhythmias [see Warnings and Precautions (5.7) ] Renal toxicity [see Warnings and Precautions (5.8) ] Bowel obstruction and perforation [see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence of ≥ 20%) are: ( 6.1 ) FL: infections, neutropenia, nausea, constipation, cough, and fatigue

DLBCL

infections, neutropenia, alopecia, nausea, and anemia CLL: infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described below reflect exposure to RITUXAN HYCELA in 892 patients in four controlled trials with exposures ranging from a single injection up to 27 months of treatment. The population included 382 patients with follicular lymphoma (FL), 369 patients with diffuse large B-cell lymphoma (DLBCL), and 141 patients with chronic lymphocytic leukemia (CLL). The median age was 60 years (range: 18 • 85 years, 53% were male, and 84% were White. In the SABRINA study patients with FL received a full dose of a rituximab product by intra... [See full FDA label]

💊 Drug Interactions ›

Renal toxicity when used in combination with cisplatin. ( 5.8 )

🤰 Pregnancy ›

8.1 Pregnancy Risk Summary Based on human data, rituximab-containing products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero (see Clinical Considerations ) . There are no available data on RITUXAN HYCELA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, intravenous administration of a rituximab product to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid B cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Reduced fetal weight and increased fetal lethality were observed following subcutaneous administration of hyaluronidase human in mice at a dose > 2700 times higher than the human dose. Comparable systemic exposure levels could occur in a pregnant patient following accidental intravenous administration of an entire vial of RITUXAN HYCELA (see Data ) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk in the U.S. general population of major birth defects is 2% • 4% and of miscarriage is 15% • 20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal Adverse Reactions Observe newborns and infants for signs of infection and manage accordingly. Data Human Data Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than 6 months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Animal Data RITUXAN HYCELA for subcutaneous injection contains rituximab and hyaluronidase human [see Description (11) ] . Rituximab Product: An embryo-fetal developmental toxicity study was ... [See full FDA label]

👶 Pediatric Use ›

8.4 Pediatric Use The safety and effectiveness of RITUXAN HYCELA in pediatric patients have not been established.

👴 Geriatric Use ›

8.5 Geriatric Use Of the total number of subjects in the SABRINA, MabEase, and SAWYER studies, 37% were 65 and over, while 10% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

🔬 Mechanism of Action ›

12.1 Mechanism of Action Rituximab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis. Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC). Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase human increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase human in RITUXAN HYCELA acts locally. The effects of hyaluronidase human are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours. Hyaluronidase human has been shown to increase the absorption rate of a rituximab product into the systemic circulation when given in the subcutis of Göttingen Minipigs.

📊 Pharmacokinetics ›

12.3 Pharmacokinetics The geometric mean rituximab exposures are provided in Table 4 . The pharmacokinetic properties of rituximab following the administration of RITUXAN HYCELA in the approved indications are provided in Table 5 . The elimination of rituximab was characterized by a time-dependent process that occurred early in therapy and a time-independent process. Table 4: Rituximab Exposure Values following Subcutaneous Administration of RITUXAN HYCELA Pharmacokinetic parameters are presented as geometric mean unless otherwise specified. Study For study design information, see Clinical Studies (14) . Cycle Rituximab FL RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) C max , mcg/mL (CV%) SABRINA 7 237 (29.4) 18 156 (24.7) Based on predicted values C trough , mcg/mL (CV%) 7 122.2 (55.3) 18 45.5 (53.6) AUC TAU , mcg∙day/mL (CV%) 7 3779 (33.7) 18 5000 (34.3) CLL RITUXAN HYCELA 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) C max , mcg/mL (CV%) SAWYER 6 202 (36.1) C trough , mcg/mL (CV%) 5 97.5 (42.6) AUC TAU , mcg∙day/mL (CV%) 5 4088 (34.2) In the SABRINA study, the geometric mean C trough in the RITUXAN HYCELA arm was higher than in the rituximab arm with a geometric mean ratio (C trough , RITUXAN HYCELA/C trough , rituximab) of 1.52 (90% CI: 1.36, 1.70) at Cycle 7 [see Clinical Studies (14.1) ] . In the SAWYER study, the geometric mean C trough in the RITUXAN HYCELA arm was higher than in the rituximab arm with an adjusted geometric mean ratio of 1.53 (90% CI: 1.27 • 1.85) at Cycle 5 [see Clinical Studies (14.3) ] . Table 5: Pharmacokinetic Parameters of Rituximab following Subcutaneous Administration of RITUXAN HYCELA Parameters represented as geometric mean (%CV) unless otherwise specified FL CLL Absorption Absolute Bioavailability Compared to a rituximab product administered intravenously 0.646 (0.634 • 0.659 95% CI ) 0.634 (0.602 • 0.665 ) Distribution Volume of Central compart... [See full FDA label]

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💊 RITUXAN HYCELA

1.2 Diffuse Large B-Cell Lymphoma (DLBCL) RITUXAN HYCELA is indicated for the treatment of adult patients w... [See full FDA label]

2 DOSAGE AND ADMINISTRATION For subcutaneous use only ( 2.1 ) All patients must receive at least one full dose of a rituximab product by intravenous infusion before receiving RITUXAN HYCELA by subcutaneous injection ( 2.1 ).

4 CONTRAINDICATIONS None None.

8.4 Pediatric Use The safety and effectiveness of RITUXAN HYCELA in pediatric patients have not been established.